Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

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Pyro70
Posts: 135
Joined: Mon Jan 21, 2019 4:25 pm

Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Mon Jun 17, 2019 1:05 am

All,

This is a very early study with only 24 MSS CRC patients but the results are very encouraging. The more I look into it the more promising the results are and I felt the need to share this news.

In a nutshell the combination of Stivarga/regorafenib + Nivolumab had an Objective Response rate (tumor shrinkage of 30% and no new lesions) in 33% of MSS CRC patients (n=24). But that’s not all. If you look at the waterfall for CRC, 87% (21/24) of MSS CRC patients had stable disease, with only (5/24) having any significant lesion growth. Furthermore if you look at the waterfall for all patients, the best responders were on the lowest dose (80mg) and this is what’s recommended for further study. The standard dose for regorafenib (monotherapy) was 160mg, recently the Redos study showed starting at 80mg and escalating weekly to 160mg unless toxicity is reached is superior to the standard dose. This immunotherapy combination recommends using the lowest possible dose of regorafenib (and hence fewer side effects).

The biggest downside of this study is the short follow up (less than a year) duration so we don’t yet know if the responses are as durable in as say Pembrolizumab for MSI patients. But if you look at the spider plot for tumor response, it looks that at least for partial response patients the response may be somewhat durable. We’ll know more once the data matures, and I’m sure there will be many more studies looking into this. I think it’s fair to say this is by far the best response to immunotherapy in MSS we’ve seen.

Here is the best part. Regorafenib is already approved for advanced mCRC. Nivolumab or Keytruda are already on the market so any doctor can prescribe them right now, off label. (Nivolumab and Pembrolizumab are both Pd-1 inhibitors so they should be interchangeable). The main problem will be insurance reimbursement for the off-label immunotherapy. I’ve already heard of oncologists trying this with patients based on this study’s data. If I could handle Regorafenib and I had no other options, I would try this right now. If I have a therapy that’s working, I’d likely try to wait 6-12 months for more mature data, or tough it out until progression.

Image

Image

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)
https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.611
Last edited by Pyro70 on Mon Jun 17, 2019 2:10 pm, edited 1 time in total.
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

lovelife789
Posts: 140
Joined: Thu Aug 24, 2017 5:28 am

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby lovelife789 » Mon Jun 17, 2019 8:11 am

Thanks Pyro70, it does sound encouraging!
F/38 - Dx 8 Mar 17, CEA 189.5
Stage IV Sig. Colon, Liver mets, T3N0M1a, KRAS NRAS Wild, G2=Mod. differentiated
3/17- 6/17 - 6 rounds of FOLFOX + Erbitux - CEA 2.5
7/17 - 1st Liver resect/Colon/Gall, all clear margin
8/17 - 2nd Liver resec
9-12/17' - completed 13 rounds of FOLFOX - CEA 1.0
1/18 - 6/30 - NED
6/30 - PET SCAN showed a lung nodule that grew from 5mm to 8mm - CEA 1.0
8/30 - VATs
8/30 - 4/30 - NED
5/28 - uptake seen in 1 x PALN, 1x common iliac, cloudy in Liver
FOLFIRI + Avastin

User avatar
Jack&KatiesMommy
Posts: 589
Joined: Wed Dec 21, 2011 1:08 pm
Location: Columbus, OH

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Jack&KatiesMommy » Mon Jun 17, 2019 10:41 am

This is great, Pyro! Please keep us updated on any new developments! This is exactly the kind of thing that could turn into a game changer for so many of us!
Cynthia
Cynthia
Mommy to Jack (8) now (16) and Katie (4) now (12)
(My Most Precious Things)
Dx 8/11 Stage IV CRC (liver mets) CEA 2,600+
9/11 Folfiri 2/12: Failed Liver Resection
5/12 HAI pump/removed primary
4/13 Liver Resection
8/13-12/15 (10) RFAs lungs
5/17: Upper Left Lobe of lung resected.
02/18: 3 new mets lymph nodes lung:
05/18: Keytruda (MSS w/Intermediate TMB): CEA: 66.4, 39.2, 23.8, 13, 3.5 1.8, 1.0, 2.8 3.9, 5.0, 5.6, 1.5, .8, .8, 1.1, 1.1, .7
7/18; 9/18; 11/18; 2/19 Clear CT scans

Claudine
Posts: 64
Joined: Tue Mar 12, 2019 2:41 pm
Location: Montana

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Claudine » Mon Jun 17, 2019 11:49 am

Thanks for posting this Pyro70! Any promising research avenue is wonderful to read about.

Claudine
Wife of Dx 04/2018 (51 yo). MSS, KRAS mutated G12A
No primary, lytic tumor L4 vertebrae, CEA 10
Radiation 04/2018
Resection small intestine 05/18 (activity on PET scan, but no cancer found)
Xelox * 6, 05/2018 to 10/2018
6.7 cm hypermetabolic left adrenal mass 03/14/2019, 4.4 cm 05/21/2019
SBRT L4 02/2019
Folfiri + Avastin
CEA 58 03/15, 17 03/29, 10 04/12, 6.4 04/26, 5 05/10, 4.8 05/23, 4.2 06/07, 3.6 06/21, 3.2 07/07
Scan 05/21: Multiple small lung nodules shrinking or stable compared to 03/14 scan.

Pyro70
Posts: 135
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Mon Jun 17, 2019 2:00 pm

Made an accidental pocket post. Can’t figure out how to delete so. So I edited it. Sorry
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

tbt4snow
Posts: 24
Joined: Sat Oct 27, 2018 3:16 pm
Facebook Username: Tina tran

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby tbt4snow » Mon Jun 24, 2019 9:36 am

Pyro70 wrote:All,

This is a very early study with only 24 MSS CRC patients but the results are very encouraging. The more I look into it the more promising the results are and I felt the need to share this news.

In a nutshell the combination of Stivarga/regorafenib + Nivolumab had an Objective Response rate (tumor shrinkage of 30% and no new lesions) in 33% of MSS CRC patients (n=24). But that’s not all. If you look at the waterfall for CRC, 87% (21/24) of MSS CRC patients had stable disease, with only (5/24) having any significant lesion growth. Furthermore if you look at the waterfall for all patients, the best responders were on the lowest dose (80mg) and this is what’s recommended for further study. The standard dose for regorafenib (monotherapy) was 160mg, recently the Redos study showed starting at 80mg and escalating weekly to 160mg unless toxicity is reached is superior to the standard dose. This immunotherapy combination recommends using the lowest possible dose of regorafenib (and hence fewer side effects).

The biggest downside of this study is the short follow up (less than a year) duration so we don’t yet know if the responses are as durable in as say Pembrolizumab for MSI patients. But if you look at the spider plot for tumor response, it looks that at least for partial response patients the response may be somewhat durable. We’ll know more once the data matures, and I’m sure there will be many more studies looking into this. I think it’s fair to say this is by far the best response to immunotherapy in MSS we’ve seen.

Here is the best part. Regorafenib is already approved for advanced mCRC. Nivolumab or Keytruda are already on the market so any doctor can prescribe them right now, off label. (Nivolumab and Pembrolizumab are both Pd-1 inhibitors so they should be interchangeable). The main problem will be insurance reimbursement for the off-label immunotherapy. I’ve already heard of oncologists trying this with patients based on this study’s data. If I could handle Regorafenib and I had no other options, I would try this right now. If I have a therapy that’s working, I’d likely try to wait 6-12 months for more mature data, or tough it out until progression.

Image

Image

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)
https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.611

Hi Pyro70,
Can I have a copy of this article? I spoke to my oncologist about this and he think I would benefit from this treatment. Can I PM you about this?
Thanks.
DX: CC stage 4/w ovaries & omentum mets in 12/17 49/F
High grade pT3N1bM1b sigmoid Adenocarcinoma colon
MSS-h TMB=16, NRAS-mutant
Lymph nodes: 1/2 left colic; 3/8 regional
12/2017: Exploratory laparotomy & resect of sigmoid & ovaries
Folfox/avastin 12 sessions from 1/8-6/18. 6/18 CEA 2.1
1/19: CT shows peri mets;
CEA: 12/18 5.1, 1/7/19 7.9; 1/15/19 9.1; 1/30/19: 10.6
4/3/2019 CRS/HIPEC after 4 Folfiry sessions...

Pyro70
Posts: 135
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Mon Jun 24, 2019 1:44 pm

tbt4snow wrote:
Pyro70 wrote:All,

This is a very early study with only 24 MSS CRC patients but the results are very encouraging. The more I look into it the more promising the results are and I felt the need to share this news.

In a nutshell the combination of Stivarga/regorafenib + Nivolumab had an Objective Response rate (tumor shrinkage of 30% and no new lesions) in 33% of MSS CRC patients (n=24). But that’s not all. If you look at the waterfall for CRC, 87% (21/24) of MSS CRC patients had stable disease, with only (5/24) having any significant lesion growth. Furthermore if you look at the waterfall for all patients, the best responders were on the lowest dose (80mg) and this is what’s recommended for further study. The standard dose for regorafenib (monotherapy) was 160mg, recently the Redos study showed starting at 80mg and escalating weekly to 160mg unless toxicity is reached is superior to the standard dose. This immunotherapy combination recommends using the lowest possible dose of regorafenib (and hence fewer side effects).

The biggest downside of this study is the short follow up (less than a year) duration so we don’t yet know if the responses are as durable in as say Pembrolizumab for MSI patients. But if you look at the spider plot for tumor response, it looks that at least for partial response patients the response may be somewhat durable. We’ll know more once the data matures, and I’m sure there will be many more studies looking into this. I think it’s fair to say this is by far the best response to immunotherapy in MSS we’ve seen.

Here is the best part. Regorafenib is already approved for advanced mCRC. Nivolumab or Keytruda are already on the market so any doctor can prescribe them right now, off label. (Nivolumab and Pembrolizumab are both Pd-1 inhibitors so they should be interchangeable). The main problem will be insurance reimbursement for the off-label immunotherapy. I’ve already heard of oncologists trying this with patients based on this study’s data. If I could handle Regorafenib and I had no other options, I would try this right now. If I have a therapy that’s working, I’d likely try to wait 6-12 months for more mature data, or tough it out until progression.

Image

Image

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)
https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.611

Hi Pyro70,
Can I have a copy of this article? I spoke to my oncologist about this and he think I would benefit from this treatment. Can I PM you about this?
Thanks.


Of course feel free to PM me. Unfortunately, I don’t have more material than the posters I shared and the abstract link below. The abstract mentions an updated bio marker analysis, I’d love to see it, but haven’t seen anyone post about it.

I’m excited to see some oncologists pursue this off-label and have heard others doing so as well.

I can’t tell from your Signature. Are you Microsatellite Stable or Do you have Microsatellite instability? Either way, with your TMB immunotherapy is worth a shot.

https://meetinglibrary.asco.org/record/172421/abstract
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

tbt4snow
Posts: 24
Joined: Sat Oct 27, 2018 3:16 pm
Facebook Username: Tina tran

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby tbt4snow » Mon Jun 24, 2019 7:11 pm

Thanks Pyro70, I’m MSS. I’m hoping dr will work on insurance coverage soon for nivolumab. My current treatment with folfox and oxaliplatin give me really bad neuropathies right after the 1st treatment so this can’t go far.
DX: CC stage 4/w ovaries & omentum mets in 12/17 49/F
High grade pT3N1bM1b sigmoid Adenocarcinoma colon
MSS-h TMB=16, NRAS-mutant
Lymph nodes: 1/2 left colic; 3/8 regional
12/2017: Exploratory laparotomy & resect of sigmoid & ovaries
Folfox/avastin 12 sessions from 1/8-6/18. 6/18 CEA 2.1
1/19: CT shows peri mets;
CEA: 12/18 5.1, 1/7/19 7.9; 1/15/19 9.1; 1/30/19: 10.6
4/3/2019 CRS/HIPEC after 4 Folfiry sessions...

Pyro70
Posts: 135
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Mon Jun 24, 2019 7:45 pm

tbt4snow wrote:Thanks Pyro70, I’m MSS. I’m hoping dr will work on insurance coverage soon for nivolumab. My current treatment with folfox and oxaliplatin give me really bad neuropathies right after the 1st treatment so this can’t go far.



Do you mind me asking, did you suggest this regiment or was it your oncologist’s idea?

I think it’s hard to do more than 12 rounds of oxaliplatin without risking permanent neuropathy. The problem with oxi is that the neuropathy can get worse after stopping treatment, so you don’t even know how bad it is while receiving treatment.
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

tbt4snow
Posts: 24
Joined: Sat Oct 27, 2018 3:16 pm
Facebook Username: Tina tran

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby tbt4snow » Mon Jun 24, 2019 7:59 pm

I informed my onc of the neuropathies problem and he said this can’t go on for long so we have to look at other options. So I showed him your post. He reviewed and agreed we should pursue this option. Thank you so much. This gives me hope.
DX: CC stage 4/w ovaries & omentum mets in 12/17 49/F
High grade pT3N1bM1b sigmoid Adenocarcinoma colon
MSS-h TMB=16, NRAS-mutant
Lymph nodes: 1/2 left colic; 3/8 regional
12/2017: Exploratory laparotomy & resect of sigmoid & ovaries
Folfox/avastin 12 sessions from 1/8-6/18. 6/18 CEA 2.1
1/19: CT shows peri mets;
CEA: 12/18 5.1, 1/7/19 7.9; 1/15/19 9.1; 1/30/19: 10.6
4/3/2019 CRS/HIPEC after 4 Folfiry sessions...

Pyro70
Posts: 135
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Mon Jun 24, 2019 9:29 pm

tbt4snow wrote:I informed my onc of the neuropathies problem and he said this can’t go on for long so we have to look at other options. So I showed him your post. He reviewed and agreed we should pursue this option. Thank you so much. This gives me hope.


Amazing. Please keep us posted on how it’s going. I wish you the best!
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

Rock_Robster
Posts: 186
Joined: Thu Oct 25, 2018 5:27 am
Location: Melbourne, Australia

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Rock_Robster » Mon Jun 24, 2019 9:58 pm

tbt4snow wrote:I informed my onc of the neuropathies problem and he said this can’t go on for long so we have to look at other options. So I showed him your post. He reviewed and agreed we should pursue this option. Thank you so much. This gives me hope.

That’s pretty impressive guys - well done! Best of luck tbt4snow
Male 37; Melbourne, Australia.
10/2018 Dx 3.5 cm RC adenocarcinoma, 12cm from AV
Mod diff (G2), EMVI+, LVI+, PNI-
3 local LN; 4 liver mets, resectable
pT3pN1apM1a; Stage IVa. MSS, NRAS (G13R)
CEA: Oct-18= 12; Nov-18= 14, Mar-19= 2.4, Aug-19 <2.0
11/18 - FOLFOX x 6
3/19 - Liver resection (open)
4-5/19 - 25 x pelvic radiation w Xeloda; complete metabolic response (TRG 3)
07/19 - ULAR (robotic), temp ileo. 1/27 LN positive
08/19 - Missed liver spot; plan to resect after chemo
08/19 - FOLFOX or FOLFORI x 4

Pyro70
Posts: 135
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Thu Jun 27, 2019 8:35 pm

I’m linking a video that has a good discussion on this combo. One thing the presenter makes clear is that these results were really unexpected and promising, but will need to be validated (including in non-Japanese patients). He also speaks to the impressive results of the combo versus mono therapy for each drug individually (responses are less 5% for both drugs given as mono therapy).

https://youtu.be/OD9G2GnbUxk

The relevant discussion starts at 42:30.
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

ForDad
Posts: 82
Joined: Mon Feb 03, 2014 4:13 pm
Location: California

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby ForDad » Fri Jul 05, 2019 3:09 pm

Thank you for starting this thread, Pyro70. Today, our oncologist recommended the Regorafenib (Stivarga) + Nivolumab (Opdivo) regimen for my dad. Our onc cited this study and informed us that he has several other patients who will start this regimen under his care.

My dad will start this regimen in about two weeks as that’s how long it might take for the paperwork to go through. Maker of Opdivo will provide it at no charge after receiving proof of insurance rejection. Since Opdivo is currently not approved for MSS patients, we expect his insurance to reject the claim.

Background info:

My dad has been on Avastin for the past three years to keep his lung mets in check. The mets have grown in recent months, so my dad went on FOLFIRI + Avastin. CT scan after four rounds showed stable disease. My dad has been absolutely miserable on FOLFIRI + Avastin and really wanted to try something else. Since being diagnosed in 2013, he has had 89 rounds of chemo and is physically and mentally exhausted.

I will post updates after he starts treatment. Best luck to everyone on this journey.
Daughter to Dad age 67 @dx, Dec. 2013 (now 73)
Stage IV cecum, 4 liver mets, CEA 21.8
MSS, KRAS mutant (G13D), MLH1 mutant (V384D), and TP53 mutant (G245S)
1/14 FOLFOXIRI, 2x
2/14 FOLFOX, 1x
3/14 Right hemicolectomy, 2/38 nodes
4/14 FOLFOX, 4x
8/14 Liver resection
9/14 Liver tumor growth: microwave ablation
10/14 FOLFIRI, 6x
1/15 NED
2/16 8 to 10 lesions in lungs
3/16 Avastin + 5FU, 72x
4/19 Growth in lungs, lymph nodes. FOLFIRI + Avastin, 4x (CEA 12.4)
7/19 Started Stivarga + Opdivo

Pyro70
Posts: 135
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Fri Jul 05, 2019 4:16 pm

ForDad wrote:Thank you for starting this thread, Pyro70. Today, our oncologist recommended the Regorafenib (Stivarga) + Nivolumab (Opdivo) regimen for my dad. Our onc cited this study and informed us that he has several other patients who will start this regimen under his care.

My dad will start this regimen in about two weeks as that’s how long it might take for the paperwork to go through. Maker of Opdivo will provide it at no charge after receiving proof of insurance rejection. Since Opdivo is currently not approved for MSS patients, we expect his insurance to reject the claim.

Background info:

My dad has been on Avastin for the past three years to keep his lung mets in check. The mets have grown in recent months, so my dad went on FOLFIRI + Avastin. CT scan after four rounds showed stable disease. My dad has been absolutely miserable on FOLFIRI + Avastin and really wanted to try something else. Since being diagnosed in 2013, he has had 89 rounds of chemo and is physically and mentally exhausted.

I will post updates after he starts treatment. Best luck to everyone on this journey.


Thank you for sharing this info. It’s good to know some of the manufacturer is willing to provide the drug for free. I know we would all appreciate you sharing your experience with this combo. I’m hoping for you, and all of us, that the Japanese results are real and you’ll see a durable response with limited side effects.

FYI, I’m reposting from the MSS Facebook group. There are also two trials one can join to test this combo. Pembrolizumab should be equivalent to nivolumab and there is a trial in Southern California and Florida. There is also a trial recruiting in Florida for reg + Opdivo.

NCT03712943 (rego + nivolumab (Brand name Opdivo; anti PD-1))

NCT03657641 (rego + pembrolizumab (Brand name Keytruda (anti PD-1))

Interesting there is also this trial below that is completed, that I would love to see the results for:
NCT03081494 (rego + spartalizumab/PDR001 (experimental anti PD-1 by Novartis))
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak


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